Methods of producing antiarthritic activity using 3-substituted phenyl-2-thio-1,3-thiazane-2,4-dione

ABSTRACT

PHARMACEUTICAL COMPOSITIONS HAVING ANTIARTHRITIC ACTIVITY WHICH COMPRISE A 3-SUBSTITUTED PHENYL-2-THIO-1,3THIAZANE-2,4-DIONE AND METHODS OF PRODUCING ANTIARTHRITIC ACTIVITY BY ADMINISTERING INTERNALLY SAID COMPOSITIONS.

United States Patent Office 3,781,434 Patented Dec. 25, 1973 3,781,434METHODS OF PRODUCING ANTIARTHRITIC AC- TIVITY USING 3-SUBSTITUTEDPHENYL-Z- THIO-1,3-THIAZANE-2,4-DIONE Charles E. Berkolf, HuntingdonValley, Blaine M. Sutton,

Hatboro, and Donald T. Walz, Drexel Hill, Pa., assignors to SmithklineCorporation, Philadelphia, Pa. No Drawing. Filed Sept. 17, 1971, Ser.No. 181,610 Int. Cl. A61k 27/00 US. Cl. 424-246 4 Claims ABSTRACT OF THEDISCLOSURE Pharmaceutical compositions having antiarthritic activitywhich comprise a 3-substituted phenyl-2-thio-l,3- thiazane-2,4-dione andmethods of producing antiarthritic activity by administering internallysaid compositions.

This invention relates to novel pharmaceutical compositions havingantiarthritic activity and to methods of producing antiarthriticactivity by administering said compostions. More specifically, thecompositions of this invention comprise a 3-substitutedphenyl-Z-thio-1,3-thiazane- 2,4-dione as the active medicament.

The novel pharmaceutical compositions of this invention, in dosage unitform, comprise a nontoxic pharmaceutical carrier and a 3-substitutedphenyl-2-thio-1,3- thiazane-2,4-dione of the following generalstructural formula:

s 1 f s R Q t FORMULA I wherein R represents halogen such as chlorine,bromine or fluorine, preferably chlorine and in the 4-position, ortrifluoromethyl.

The compounds of Formula I above are either known or are prepared by thefollowing synthetic method. An isothiocyanate of the formula iscondensed with fi-mercaptopropionic acid in aqueous trimethyla'minesolution at room temperature togive a B- (thiocarbamoylthio)-propionicacid of the formula which is converted to the desired thiazane productby heating on a steam bath with acetic anhydride containing a few dropsof sulfuric acid. The isothiocyanate starting materials are prepared,for example, by the reaction of the required aniline with thiophosgeneeither in aqueous solution or in chloroform. Reference may be made alsoto the US. Pat. 2,727,035 and Helv. Chim. Acta, 48, 1414 (1965).

The antiarthritic activity of the compositions of this invention ismeasured by the ability of the active medicament to inhibitadjuvant-induced polyarthritis in rats. The active medicaments ofFormula I produce marked inhibition of the development of adjuvantarthritis in rats at daily oral doses of from 25 mg. to 50 mg. perkilogram of body weight. Adjuvant arthritis in rats is produced by asingle injection of 0.75 mg. of Mycobacterium butyricum suspended inwhite paraflin (N.F.) into a hindpaw (left footpad). The injected legbecomes inflamed and reaches a maximum volume in 3-5 days (primarylesion). The animals exhibit a decrease in body weight gain during thisinitial period. Adjuvant arthritis (secondary phase) occurs after adelay of approximately 10 days and is characterized by inflammation ofthe noninjected sites (right hind leg), decrease in body weight gain andfurther increases in the volume of the injected hind leg. The compoundsof Formula I administered in the doses described above beginning on theday of adjuvant injection and continuing for 17 days, thereafter,exclusive of days 4, 5, 11 and 12 protect the animals againstdevelopment of both primary and secondary lesions of adjuvant arthritis.

The utility of the compositions of this invention is further enhanced bythe failure of the compounds of Formula I to produce gastric erosions inrats at doses up to 200 mg./kg. and any observable eifects in a rat doserange at 300 mg./kg. as demonstrated in standard pharmacological testprocedures.

The pharmaceutical compositions of this invention are prepared inconventional dosage unit forms by incorporating an amount of a compoundof Formula I suflicient to produce antiarthritic activity with anontoxic pharmaceutical carrier according to accepted procedures.Preferably the compositions will contain a 1,3-thiazane of Formula I inan amount of from about 25 mg. to about 150 mg. per dosage unit.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliceoil, Water and the like. Similarly the carrier or diluent can includeany time delay material well known to the art, such as glycerylmonostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used the preparation can be ta'bleted, placed in a hardgelatin capsule in pow der or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. If a liquid carrier is used, thepreparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or an aqueous ornonaqueous liquid suspension.

The pharmaceutical dosage unit forms described hereinabove excludesimple non-sterile solutions of the active medicament in water or incommon organic solvents and exclude simple aqueous suspensions of theactive medicament in the absence of a suspending agent.

The method in accordance with this invention comprises administeringinternally to an animal organism a 1,3-thiazane of Formula I above,usually combined with a pharmaceutical carrier, in an amount suflicientto produce antiarthritic activity. The active medicament will beadministered in a dosage unit, preferably in an amount of from about 25mg. to about 150 mg. The route of administration may be orally orparenterally, the oral route being preferred. Advantageously equal oraldoses will be administered three times daily with the daily dosageregimen being from about mg. to about 450 mg. When the method describedabove is carried out antiarthritic activity is produced with a minimumof side elfects.

The pharmaceutical preparations are made following the conventionaltechniques of the pharmaceutical chemist involving mixing, granulatingand compressing when necessary or variously mixing and dissolving theingredients as appropriate to the desired end product.

The following examples illustrate the preparation of compounds ofFormula I and their incorporation into pharmaceutical compositions ofthis invention, and as such are not to be considered as limiting theinvention set forth in the claims appended hereto.

PREPARATION To a mixture of p-fluorophenylisothiocyanate (15.3 g., 0.1m.) and fi-mercaptopropionic acid (10.6 g., 0.1 m.), is added 100 ml. of25% aqueous trimethylamine with stirring. Stirring is continued at roomtemperature for 20 minutes until the reaction mixture becomeshomogeneous and is then made acidic with concentrated hydrochloric acidto give B-[N-(p-fiuorophenyl)-thiocarbamoylthio]- propionic acid, M.P.136140 C.

In a similar manner,

p- [N- (p-chlorophenyl -thiocarb amoylthio] -propionic acid,

18- [N- (m-trifiuoromethylphenyl) -thiocarbamoylthio] propionic acid,

13- [N- (m-chlorophenyl) -thiocarbamoylthio] -propionic acid,

8- [N- (o-chlorophenyl -thiocarbamoylthio] -propionic acid, and

p- [N- (p-bromophenyl -thiocarbamoylt-hio] -propionic acid are prepared.

Example 1 A mixture of B-[N(p-fiuorophenyl)-thiocarbamoylthioJ-propionicacid (8.0 g., 0.031 m.), 30 ml. of acetic anhydride and 2-3 drops ofconcentrated sulfuric acid is heated on a steam bath for minutes. Theresulting homogeneous solution becomes solid on cooling in an ice bath.The product is separated by filtration, recrystallized from glacialacetic acid and boiled with water to get rid of traces of acetic acidyielding 3-(4'-fluorophenyl)-2-thiol,3-thiazane-2,4-dione, M.P. l56158C.

Example 2 A mixture offi-[N-(m-trifiuoromethylphenyl)thiocarbamoylthio]-propionic acid (6.0g., 0.0194 m.), 25 ml. of acetic anhydride, and 2 drops of concentratedsulfuric acid is heated on a steam bath until the reaction mixturebecomes a homogeneous solution (about 10-15 minutes). The product whichcomes out of the solution on cooling in an ice-bath is recrystallizedfrom glacial acetic acid, acetic anhydride, and is then boiled withwater to get rid of traces of acetic anhydride. This gives3-(3-trifiuoromethylphenyl)-2-thi0-1,3-thiazane-2,4-dione, M.P. 222- 224C.

Example 4 Ingredients: Mg./tablet 3 (4' chlorophenyl)2-thio-1,3-thiazane-2,4-

dione 25 Calcium sulfate, dihydrate 150 Sucrose 25 Starch 15 Talc 5Stearic acid 3 The sucrose, calcium sulfate and 3-(4-chlorophenyl-2-thio-1,3-thiazane-2,4-dione are thoroughly mixed and granulated with hot10% gelatin solution. The wetted mass is passed through #6 mesh screendirectly onto drying trays. The granules are dried at F. and passedthrough a #20 mesh screen, mixed with the starch, talc and stearic acid,and compressed into tablets.

Example 5 Ingredients: Mg./capsule 3 (4 chlorophenyl)2-thio-1,3-thiazane-2,4-

dione Magnesium stearate 5 Lactose 300 The above ingredients arescreened through a #40 mesh screen, mixed and filled into #0 hardgelatin capsules.

What is claimed is:

1. A method of treating arthritis which comprises administeringinternally to an animal in need of such treatment in an amountsufiicient to produce antiarthritic activity a 3-substitutedphenyl-Z-thio-1,3-thiazane-2,4- dione of the formula:

in which R is chlorine, bromine, fluorine or trifluoromethyl.

2. The method according to claim 1 in which R is chlorine.

3. The method according to claim 2 in which R is in the 4'-position.

4. The method according to claim 3 in which the active medicament isadministered orally in a daily dosage regimen of from about 75 mg. toabout 450 mg.

References Cited UNITED STATES PATENTS 12/ 1955 Bowers et a1 260243OTHER REFERENCES Garraway, J. Chem. Soc. (1961), pp. 3733-5. Cherbuliezet 211., Helv. Chim. Acta 48, pp. 1414-1423 (1965).

ALBERT T. MEYERS, Primary Examiner A. I. ROBINSON, Assistant Examiner

